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Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

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Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer International Journal of Molecular Sciences Review Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer Zhaodi Zheng and Guorong Li * Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan 250014, China; [email protected] * Correspondence: [email protected]; Tel.: +86-531-8618-2690 Received: 24 January 2020; Accepted: 17 February 2020; Published: 20 February 2020 Abstract: Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy. Keywords: pyroptosis; GSDMD; GSDME; inflammatory disease; cancer therapy 1. Introduction Many disease states are cross-linked with cell death. The Nomenclature Committee on Cell Death make a series of recommendations to systematically classify cell death [1,2]. Programmed Cell Death (PCD) is mediated by specific cellular mechanisms and some signaling pathways are activated in these processes [3]. Apoptosis, autophagy and programmed necrosis are the three main types of PCD [4], and they may jointly determine the fate of malignant tumor cells. Pyroptosis is a form of programmed necrosis and was firstly described in myeloid cells infected by pathogens or bacteria in 1992 [5–7]. It is thought to play a crucial role in the clearance of multiple bacterial and viral infections through removing intracellular replication niches and improving the host’s defensive responses [8]. Pyroptotic death is an inflammatory form of PCD characterized by cellular swelling and rupture, lysis and release of pro-inflammatory molecules such as Interleukin 1β and Interleukin 18 (IL-1β and IL-18) [9,10]. On one hand, pyroptosis has been regarded as exclusive to specialized immune normal cells (such as macrophages, monocytes and dendritic cells) [11,12] and non-immune cell types (such as intestinal epithelial cells, human trophoblasts and hepatocyte cells) because of its inflammatory role [13]. Appropriate inflammatory responses have certain benefits to humans, and the release of cytokines may contribute to tissue angiogenesis [14]. Overactivated pyroptosis can result in a massive inflammatory response leading to inappropriate repair for damaged tissue and organ, causing inflammatory diseases [9,15,16]. However, the long-term exposure of normal tissues to the inflammatory environment may increase the risk of cancers (such as colorectal cancer) [9,15]. It is needed to explore the effect of the blockage of pyroptosis for treating inflammatory factors-driven disease [17,18]. On the other hand, resisting cell death is the important hallmark of cancers [19]. Induction of cancer cell pyroptosis by various stimulations can eliminate malignant cells [20–24]. Although pyroptotic death is often harmful to normal tissues, it can be beneficial to cancer treatment. Int. J. Mol. Sci. 2020, 21, 1456; doi:10.3390/ijms21041456 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 1456 2 of 16 In recent years, several studies have focused on the relationship between pyroptosis and various human diseases, especially inflammatory diseases and cancer. In this review, we put forward an overview of how the two gasdermin molecules (D and E) (GSDMD and GSDME) induce pyroptotic death. We summarize and discuss the potential effects of pyroptosis in inflammatory diseases and anticancer therapy. 2. Molecular Mechanisms of Pyroptosis Pyroptosis is induced by members of the gasdermin superfamily, including GSDMA, GSDMB, GSDMC, GSDMD and GSDME [25–30], of which, GSDMD and GSDME are widely studied in pyroptosis. These proteins have been shown to have inherent necrotic activity in their gasdermin-N domain, which is usually masked by their gasdermin-C domain [26,29,31]. Proteolytic cleavage between their gasdermin-N and -C domains releases inhibitory gasdermin-C domains, translocating necrotic gasdermin-N domain into the plasma membrane and forming oligomers [26,29,31–34]. These oligomers form transmembrane pores, allowing the secretion of inflammatory molecules, which disrupt osmotic potential to cause cell swelling with large bubbles blowing from the plasma membrane [27–29]. Of gasdermin family numbers, GSDMA, GSDMB and GSDMC proteins have a pore-forming gasdermin-N domain, but they have not been shown to be cleaved to form functional pores in response to physiological or pathological stimuli [25,26]. Only GSDMD and GSDME are cleaved by caspases between their gasdermin-N and -C domains to form membrane pores [25–30]. Generally, GSDMD, the downstream of inflammasome activation, is cleaved by inflammatory caspases (caspase1/4/5/11) to induce pyroptosis, while GSDME is cleaved by apoptotic caspase (caspase3) to cause pyroptotic death [26]. Depending on the specific signal pathway and cell types, different molecular patterns are secreted to induce pytoptosis [35]. 2.1. Mechanism of GSDMD Activation In the canonical inflammatory pathway, pattern-recognition receptors (PRR) such as Toll-like receptors (TLRs), Nod-like receptor (NLRs) and Absent in melanoma (AIMs), recognize certain pathogen-associated molecular patterns (PAMPs) and certain damaged-associated molecular patterns (DAMPs) [36,37] to activate inflammasomes [38–40]. These inflammasomes recruit adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to activate caspase1 [41]. Caspase1 can cleave GSDMD to generate the N-terminal domain of GSDMD (GSDMD-N), which permeabilizes the plasma membrane, undergoing pyroptosis [18,42–44]. GSDMD has been widely characterized for its ability to form necrotic pores in the plasma membrane. Recently, a study showed that GSDMD causes mitochondrial depolarization and leads to mitochondrial decay before causing plasma membrane rupture upon activation of the inflammasome in macrophages [45]. Rogers et al. further demonstrated that GSDMD-N can translocate to and permeabilize the mitochondrial membrane to activate BCL-2 associated X (Bax) apoptosis regulator and release cytochrome c (Cyt c), triggering the caspase3-mediated mitochondrial apoptotic pathway [46]. This study provides a link between the pyroptotic and apoptotic pathways, in which the inflammatory caspase cleavage of GSDMD targets mitochondria and activates caspase3 to induce apoptosis (Figure1). Int. J. Mol. Sci. 2020, 21, 1456 3 of 16 Figure 1. Gasdermin D (GSDMD)-mediated cell death. When physiological or pathological stimuli activates inflammasomes, ASC is recruited to lead to activation of caspase1. GSDMD is cleaved by caspase1 to release active GSDMD-N, translocating to the plasma membrane to induce pyroptosis. Meanwhile, GSDMD-N can also permeabilize the mitochondrial membrane to trigger the mitochondrial apoptotic pathway downstream of inflammasome activation, inducing cell apoptosis. A recent study also demonstrates that when GSDMD expression is too low to cause pyroptosis in certain cell types (neurons, mast cells, fibroblasts), caspase1 can induce apoptosis through the Bid-caspase9-caspase3 axis [47]. In GSDMD-deficient monocytes and macrophages, caspase1 also activates caspase3 and 7 to induce apoptosis [11]. These data suggest that the initiation of pyroptosis or apoptosis induced by caspase1 depends on the expression level of GSDMD. 2.2. Mechanism of GSDME Activation In 2017, Rogers et al. found that GSDME is specifically cleaved by caspase3 to generate its N-terminal fragment (GSDME-N), perforating plasma membrane to induce pyroptosis [29]. In response to chemotherapy drugs, caspase3 cleavage of GSDME drives pyroptosis in GSDME-expressing cells, including normal human primary cells (such as epidermal keratinocytes, placental epithelial cells and umbilical artery smooth muscle cells) and certain cancer cells (such as neuroblastoma, skin melanoma and gastric cancer cells) [21,30,48]. GSDME-negative cells display typical apoptotic death, and GSDME / mice are also protected from tissues injuries upon chemotherapy [30]. − − Subsequently, Zhou et al. revealed that iron-induced oxidative stress triggers pyroptotic death through which Bax recruited to mitochondria stimulates Cyt c release to enhance caspase9 and caspase3 activation, causing cleavage of GSDME in melanoma cells [49]. GSDME has been shown to be an important mitochondrial pore-forming protein. When extrinsic stimuli such as tumor necrosis factor-α (TNFα) bind to death receptors, caspase8 is activated to lead to cleavage of caspase3. Generation of the GSDME-N by active caspase3 can permeabilize the mitochondrial membrane to release Cyt c and induce caspase3-mediated apoptosis, which is similar to the GSDMD-induced apoptotic pathway [46,50]. Above all, GSDME cleavage of apoptotic caspase can target the plasma membrane to drive pyroptosis, and also permeabilize the mitochondrial membrane to augment the mitochondrial apoptotic pathway, both types of cell death share the apoptotic pathway (Figure2). This discovery alters our understanding
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